P702: FIRST INTERIM RESULTS OF THE PROSPECTIVE STUDY OF DOSE REDUCTION AND DISCONTINUATION OF TYROSINE KINASE INHIBITORS (READIT-2020) IN CHRONIC MYELOID LEUKEMIA PATIENTS WITH DEEP MOLECULAR RESPONSE
Authors: M. Gurianova, O. Shukhov, E. Chelysheva, A. Petrova, A. Bykova, I. Nemchenko, E. Kuzmina, N. Tsyba, L. Gavrilova, E. Stepanova, A. Kohno, A. Turkina
Journal: HemaSphere (2022)

Background: The feasibility of the one-step tyrosine kinase inhibitors (TKI) dose reduction before treatment-free remission (TFR) phase in chronic myeloid leukemia (CML) patients (pts) has been confirmed in several trials.There are no data of the prospective two-step dose reduction trials of different TKIs followed up with TFR observation.The experience of resuming TKIs at reduced doses after the molecular relapse is limited as well. Aims: To analyze the interim data of the survival without loss of major molecular response (MMR,BCR::ABL1≤0,1%) after TKI stop in CML pts taking reduced-dose TKI therapy and the probability of MMR and deep MR (DMR, BCR::ABL1≤0.01%) recovery after resuming TKIs at reduced doses (Clinicaltrials.gov NCT 04578847). Methods: The prospective trial had 2 phase:1)TKI dose reduction phase for at least 12 months (mo),2)TFR phase for at least 24 mo.TKI dose reduction consisted of 2 steps each lasting for 6 mo.The inclusion of pts was possible at any step if they met the key inclusion criteria:CML in chronic phase,age ≥18 years (y),TKI therapy duration≥ 3 y,MMR and DMR duration≥2 y and ≥1 y.The inclusion into TFR was done after the dose reduction phase in pts with a DMR duration≥2 y and ≥MR4.5 at the time of TKI stop.In case of MMR loss the TKI dose was increased by +1 level from the dose at which the MMR loss developed. Results: A total of 103 CML pts were included from Dec.2019 till Dec.2021 at different trial phases (Tab 1). Female 60%, Median (Me) age at diagnosis and at inclusion 45 y (23-74 y) and 51 y (23-74 y),respectively;ELTS score 61%:17%:1%, 21% for low,intermediate,high and unknown risk group.A history of at least one TKI stop was in 29 pts. Me TKI duration was 7 y (3-19,7 y);Me duration of MMR and DMR was 3,3 y (2-126 y) and 2,5 y (1,2-10,5 y), respectively. At baseline 69 (67%) pts received imatinib (IM) and 34 (33%) pts-second-generation (2G)TKI (Tab 1). The reasons for 2GTKI switch were treatment failure (n=12),drug toxicity (n=25),others (n=1). Sixty-four pts completed the 1st dose reduction step lasting for 6 mo. There was no MMR loss after the 1st dose reduction step. Four pts lost DMR on IM 300 mg,but three pts restored DMR in 3 mo at the same dose thereafter. Fifty-seven pts completed the 6 mo 2nd step of dose reduction.Two pts lost MMR on IM 200 mg.Nine pts lost DMR (without MMR loss):6 pts on IM 200 mg,1 pt on dasatinib (DAS) 25 mg and 2 pts on nilotinib (NIL) 200 mg. Forty-nine pts were included in TFR phase,16 pts (32,6%) had a history of at least one TKI stop.Eight pts had a history of resistance to TKI therapy.Me follow-up after TKI discontinuation was 10 mo (1-24 mo). The survival without MMR loss was 61% and 41% in pts with 1st and 2nd TKI stop,respectively (Fig 1). The survival without MMR loss was 54% after 12 mo in total group. TKI therapy was resumed at reduced doses after MMR loss:IM 200 mg(n=12),NIL 200 mg (n=4),DAS 25 mg (n=2);BOS 200 mg (n=3).The probability of recovery of MMR and DMR was 86% and 83% after 6 mo resumption of TKIs at reduced doses (Fig 2). Image:Summary/Conclusion: The 2-step dose reduction of TKIs before TFR phase is a promising approach for CML pts.Use of the reduced TKI doses in pts with DMR lasting for≥1 y is a safe treatment option under the strict molecular monitoring. The 61% survival rate without MMR loss in CML pts having the 1st TKI discontinuation after the dose reduction phase is encouraging.The high probability of MMR and DMR recovery after resuming TKIs at reduced doses allows to consider this possibility in case of the molecular relapse.